Since the abuse of amphetamine and its congeners continues to increase, we propose to extend our investigation of the neurotoxicity of these compounds. We have demonstrated profound toxic effects on the serotenergic, catecholaminergic and substance p systems after large doses of methamphetamine. As suggested by the Committee, we will compare the response of the serotonergic and catecholaminergic systems to the amphetamines in both tolerant and naive rats. In these experiments we hope to determine whether the profound neurochemical changes seen after the amphetamines are applicable to the abuser of these agents. In all studies, the actvities of tyrosine hydroxylase and tryptophan hydroxylase and concentrations of dopamine, 5-hydroxytrypatamine, their metabolites and substance P will be monitored. Recent evidence suggests that the effects of methamphetamine on the serotonergic system may differ from those of amphethamine; to explore this possibility the metabolism of methamphetamine will be inhibited and the effects compared to those observed during normal metabolism. The possible role of pterins in the neurotoxicity of the amphetamines will be thoroughly investigated. Since substance P is proposed as an excitatory neurotransmitter in the strationigral pathway and is thought to modulate the dopaminergic nigrostriatal pathway, the effects of the amphetamines on substance P will be determined. Preliminary studies reveal that substance P levels are altered by these CNS stimulants; these effects will be further characterized. Finally, we will examine the possible role of uptake and release as a factor influencing the neurotoxicity of the amphetamines. These studies will utilize release from superfused tissue slices to determine how agents such as AOAA, haloperidol and Alpha-methyltyrosine might alter the uptake of amphetamines or their releasing action. The data obtained in these studies will expand the knowledge of the biochemical mechanisms of neurotoxicity caused by commonly abused CNS stimulants.